This application addresses broad Challenge Area (15) Translational Science Topic 15-CA102 Title: Measures of Endocrine Sensitivity in Early Breast Cancer. Adjuvant endocrine therapy improves outcomes for estrogen receptor positive (ER+) early stage breast cancer. Recently aromatase inhibitors (AIs) have been shown to provide incremental benefit over tamoxifen. In neo-adjuvant endocrine therapy studies, a two-week low proliferative index (Ki-67) predicts benefit from endocrine therapy. Extremely large studies are now underway to prospectively determine if genomic profiling can select which patients need chemotherapy in addition to endocrine therapy;given the latency for recurrence and relapse, these definitive studies will take years to mature and enrolled patients will gain no additional information about their own risk of recurrence or relapse. Alternative approaches are necessary to refine therapy selection and improve outcomes for early stage breast cancer. We propose to examine dynamic tumor characteristics by imaging and tissue analysis in a brief, preoperative, 2-week, "window" study, to define AI sensitive tumors, and establish a rapid method for identification of whether this ER-targeted therapy is active at the tumor's molecular target. We will pair baseline and two-week tissue analysis of protein expression and genomic profiles with pre and post AI PET FDG and FLT dynamic quantitative measures to examine the effect of AI therapy on molecular pathways in the whole tumor in early breast cancer. This strategy has the potential to refine treatment selection for early stage breast cancer, and identify molecular pathways of sensitivity and resistance to endocrine therapy. Our proposal will demonstrate the feasibility of this approach toward personalized treatment, and potentially identify a model for the rapid study of promising agents in early breast cancer. Estrogen receptor positive (ER+) early stage breast cancer is the most commonly seen breast cancer in the US, and has an excellent rate of cure with standard therapies. However, the necessity for chemotherapy (in addition to anti-estrogen therapy) for cure of early stage tumors remains unclear, and some patients experience recurrence and/or distant metastasis despite taking indicated treatments. PUBLIC HEALTH RELEVANCE: We propose to study the response to the current standard anti-estrogen therapy, Aromatase Inhibitor (AI) therapy in the pre-operative two-week "window," using molecular imaging, and genomic profiles from tissue samples to identify mechanisms of sensitivity and resistance to AI therapy. Our studies will identify ways tumors respond to and resist AI treatment, and identify a way to rapidly obtain detailed information from patients on treatment, which could identify a method to screen new treatments aimed to overcome anti-estrogen resistance.